It is currently estimated that 36 million people worldwide are infected with HIV (UNAIDS Report 2000). Current therapies for infection use a cocktail of drugs referred to as HAART (Highly Active Antiretroviral Therapy). The cocktail contains a combination of protease and reverse transcriptase inhibitors that are specific for the virus. Despite the increased effectiveness of this treatment, drug resistance and toxicity remain serious issues. It is the goal of this proposal to develop inhibitors of HIV membrane fusion by finding molecules that can bind to the gp41 inner core domain and prevent the conformational change necessary for viral infection. By going after a different target than traditional therapy it is hoped that they may be used to complement them. A two-fold approach using both rational design methods and high throughput screening will be used to discover small molecules that can bind to the inner core of gp41. Structures will be determined using x-ray crystallography so that structure based design methods can be used to enhance binding affinities. Cell-cell fusion assay will be used to determine the ability of the molecules to inhibit membrane fusion.